Investigation of the role and mechanism of ARHGAP5-mediated colorectal cancer metastasis
Investigation of the role and mechanism of ARHGAP5-mediated colorectal cancer metastasis
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ARHGAP5介导的结直肠癌转移的作用及机制研究
DOI：
10.7150/thno.43427
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Deng, Wuguo
中科院分区：
文献类型：
--
作者：
Tian, Tian;Chen, Zhan-Hong;Deng, Wuguo
背景资料：转移性结直肠癌（CRC）是一种致死性疾病，然而，其潜在的分子机制仍不清楚，需要进一步研究。研究方法：采用RNA测序、PCR、Western blotting、免疫组化、ChIP和RNAi等方法，研究Rho GTP酶激活蛋白5（ARHGAP 5，又称p190 RhoGAP-B、p190-B）在人结直肠癌细胞和组织中的表达及其临床意义、功能作用和调控机制。在体内，使用两种基于细胞的异种移植物模型来评估ARHGAP 5在CRC转移中的作用。结果如下：在这里，我们报告ARHGAP 5表达在转移性CRC组织中显著增加，并且与患者的总生存率呈负相关。ARHGAP 5的抑制减少了体外和基于细胞的异种移植模型中的CRC细胞转移。此外，我们发现ARHGAP 5通过负调节RhoA活性促进CRC细胞上皮-间质转化。从机制上讲，cAMP反应元件结合蛋白（CREB 1）转录上调ARHGAP 5表达，减少miR-137进一步有助于CRC中ARHGAP 5 mRNA的稳定性。结论：总的来说，我们的研究强调了ARHGAP 5在CRC转移中的关键功能，从而提出了新的预后生物标志物和假设的治疗靶点。
Background: Metastatic colorectal cancer (CRC) is a lethal disease; however, the underlying molecular mechanisms remain unclear and require further study. Methods: RNA-Seq, PCR, Western blotting, immunohistochemistry, ChIP and RNAi assays were performed to investigate Rho GTPase-activating protein 5 (ARHGAP5, aslo known as p190RhoGAP-B, p190-B) expression and the clinical relevance, functional roles and regulatory mechanisms of this protein using human CRC cells and tissues. In vivo, two cell-based xenograft models were used to evaluate the roles of ARHGAP5 in CRC metastasis. Results: Here, we report that ARHGAP5 expression is significantly increased in metastatic CRC tissues and is inversely associated with patient overall survival. The suppression of ARHGAP5 reduces CRC cell metastasis in vitro and in cell-based xenograft models. Furthermore, we show that ARHGAP5 promotes CRC cell epithelial-mesenchymal transition by negatively regulating RhoA activity. Mechanistically, cAMP response element-binding protein (CREB1) transcriptionally upregulates ARHGAP5 expression, and decreased miR-137 further contributes to ARHGAP5 mRNA stability in CRC. Conclusions: Overall, our study highlights the crucial function of ARHGAP5 in CRC metastasis, thus suggesting novel prognostic biomarkers and hypothetical therapeutic targets.